Intrauterine growth restriction (IUGR) and pregnancy hypertensive disorders such as preeclampsia (PE) associated with IUGR share a common placental phenotype called “placental insufficiency”, originating in early gestation when high availability of energy is required. Here, we assess mitochondrial content and the expression and activity of respiratory chain complexes (RCC) in placental cells of these pathologies. We measured mitochondrial (mt)DNA and nuclear respiratory factor 1 ( NRF1) expression in placental tissue and cytotrophoblast cells, gene and protein expressions of RCC (real-time PCR and Western blotting) and their oxygen consumption, using the innovative technique of high-resolution respirometry. We analyzed eight IUGR, six PE, and eight uncomplicated human pregnancies delivered by elective cesarean section. We found lower mRNA levels of complex II, III, and IV in IUGR cytotrophoblast cells but no differences at the protein level, suggesting a posttranscriptional compensatory regulation. mtDNA was increased in IUGR placentas. Both mtDNA and NRF1 expression were instead significantly lower in their isolated cytotrophoblast cells. Finally, cytotrophoblast RCC activity was significantly increased in placentas of IUGR fetuses. No significant differences were found in PE placentas. This study provides genuine new data into the complex physiology of placental oxygenation in IUGR fetuses. The higher mitochondrial content in IUGR placental tissue is reversed in cytotrophoblast cells, which instead present higher mitochondrial functionality. This suggests different mitochondrial content and activity depending on the placental cell lineage. Increased placental oxygen consumption might represent a limiting step in fetal growth restriction, preventing adequate oxygen delivery to the fetus.

Estrogens regulate disparate female physiological processes, thus ensuring reproduction. Altered estrogen levels and signaling have been associated with increased risks of pregnancy failure and complications, including hypertensive disorders and low birthweight babies. However, the role of estrogens in the periconceptional period and early pregnancy is still understudied. This review aims to summarize the current evidence on the role of maternal estrogens during the periconceptional period and the first trimester of pregnancies conceived naturally and following ART. Detailed molecular mechanisms and related clinical impacts are extensively described. Data for this narrative review were independently identified by seven researchers on Pubmed and Embase databases. The following keywords were selected: ‘estrogens’ OR ‘estrogen level(s)’ OR ‘serum estradiol’ OR ‘estradiol/estrogen concentration’, AND ‘early pregnancy’ OR ‘first trimester of pregnancy’ OR ‘preconceptional period’ OR ‘ART’ OR ‘In Vitro Fertilization (IVF)’ OR ‘Embryo Transfer’ OR ‘Frozen Embryo Transfer’ OR ‘oocyte donation’ OR ‘egg donation’ OR ‘miscarriage’ OR ‘pregnancy outcome’ OR ‘endometrium’. During the periconceptional period (defined here as the critical time window starting 1 month before conception), estrogens play a crucial role in endometrial receptivity, through the activation of paracrine/autocrine signaling. A derailed estrogenic milieu within this period seems to be detrimental both in natural and ART-conceived pregnancies. Low estrogen levels are associated with non-conception cycles in natural pregnancies. On the other hand, excessive supraphysiologic estrogen concentrations at time of the LH peak correlate with lower live birth rates and higher risks of pregnancy complications. In early pregnancy, estrogen plays a massive role in placentation mainly by modulating angiogenic factor expression—and in the development of an immune-tolerant uterine micro-environment by remodeling the function of uterine natural killer and T-helper cells. Lower estrogen levels are thought to trigger abnormal placentation in naturally conceived pregnancies, whereas an estrogen excess seems to worsen pregnancy development and outcomes. Most current evidence available endorses a relation between periconceptional and first trimester estrogen levels and pregnancy outcomes, further depicting an optimal concentration range to optimize pregnancy success. However, how estrogens co-operate with other factors in order to maintain a fine balance between local tolerance towards the developing fetus and immune responses to pathogens remains elusive. Further studies are highly warranted, also aiming to identify the determinants of estrogen response and biomarkers for personalized estrogen administration regimens in ART. The impact of method of conception and serum estrogen levels on pregnancy outcome. FGR, fetal growth restriction; E2, estradiol.

OBJECTIVE: To investigate the clinical evolution of coronavirus disease 2019 (COVID-19) in hospitalized pregnant women and potential factors associated with severe maternal outcomes. METHODS: We designed a prospective multicenter cohort study of pregnant women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who were admitted to 12 Italian maternity hospitals between February 23 and March 28, 2020. Clinical records, laboratory and radiologic examinations, and pregnancy outcomes were collected. A subgroup of patients with severe disease was identified based on intensive care unit (ICU) admission, delivery for respiratory compromise, or both. RESULTS: Seventy-seven patients were included, 14 of whom had severe disease (18%). Two thirds of the patients in the cohort were admitted during the third trimester, and 84% were symptomatic on admission. Eleven patients underwent urgent delivery for respiratory compromise (16%), and six were admitted to the ICU (8%). One woman received extracorporeal membrane oxygenation; no deaths occurred. Preterm delivery occurred in 12% of patients, and nine newborns were admitted to the neonatal intensive care unit. Patients in the severe subgroup had significantly higher pregestational body mass indexes (BMIs) and heart and respiratory rates and a greater frequency of fever or dyspnea on admission compared with women with a nonsevere disease evolution. CONCLUSION: In our cohort, one in five women hospitalized with COVID-19 infection delivered urgently for respiratory compromise or were admitted to the ICU. None, however, died. Increased pregestational BMI and abnormal heart and respiratory rates on admission were associated with severe disease.

Overweight and obesity during pregnancy have been associated with increased birth weight, childhood obesity, and noncommunicable diseases in the offspring, leading to a vicious transgenerational perpetuating of metabolic derangements. Key components in intrauterine developmental programming still remain to be identified. Obesity involves chronic low-grade systemic inflammation that, in addition to physiological adaptations to pregnancy, may potentially expand to the placental interface and lead to intrauterine derangements with a threshold effect. Animal models, where maternal inflammation is mimicked by single injections with lipopolysaccharide (LPS) resembling the obesity-induced immune profile, showed increased adiposity and impaired metabolic homeostasis in the offspring, similar to the phenotype observed after exposure to maternal obesity. Cytokine levels might be specifically important for the metabolic imprinting, as cytokines are transferable from maternal to fetal circulation and have the capability to modulate placental nutrient transfer. Maternal inflammation may induce metabolic reprogramming at several levels, starting from the periconceptional period with effects on the oocyte going through early stages of embryonic and placental development. Given the potential to reduce inflammation through inexpensive, widely available therapies, examinations of the impact of chronic inflammation on reproductive and pregnancy outcomes, as well as preventive interventions, are now needed.

During intrauterine life, external stimuli including maternal nutrition, lifestyle, socioeconomic conditions, anxiety, stress, and air pollution can significantly impact fetal development. The human brain structures begin to form in the early weeks of gestation and continue to grow and mature throughout pregnancy. This review aims to assess, based on the latest research, the impact of environmental factors on fetal and neonatal brain development, showing that oxidative stress and inflammation are implied as a common factor for most of the stressors. Environmental insults can induce a maternal inflammatory state and modify nutrient supply to the fetus, possibly through epigenetic mechanisms, leading to significant consequences for brain morphogenesis and neurological outcomes. These risk factors are often synergic and mutually reinforcing. Fetal growth restriction and preterm birth represent paradigms of intrauterine reduced nutrient supply and inflammation, respectively. These mechanisms can lead to an increase in free radicals and, consequently, oxidative stress, with well-known adverse effects on the offspring’s neurodevelopment. Therefore, a healthy intrauterine environment is a critical factor in supporting normal fetal brain development. Hence, healthcare professionals and clinicians should implement effective interventions to prevent and reduce modifiable risk factors associated with an increased inflammatory state and decreased nutrient supply during pregnancy.

Purpose: Iron supplementation is associated with side effects and overload risk. We compared different regimens of iron supplementation on maternal hematological status and pregnancy outcome in a cohort of healthy pregnant women. Materials and methods: Eighty non-anemic women with a normal singleton pregnancy were recruited at 11–13 weeks and randomized into controls (C; n = 20) and groups supplemented with ferrous iron 30 mg (FI; n = 20), liposomal iron 14 mg (Sideral® Pharmanutra, Pisa PI, Italy) (LI14; n = 20) and liposomal iron 28 mg/daily (LI28; n = 20) up to 6 weeks post-partum. Longitudinal maternal blood samples for iron markers were collected. Data on birth outcome were recorded. The treatment effect was evaluated using a mixed-effect regression model. Results: Both LI28 and LI14 groups showed significantly higher hemoglobin and ferritin concentrations compared with controls. Birth weight showed a trend to increase with supplementation, resulting in higher birth weight in the LI28 group compared with controls (3499 ± 464.1 g and 3092 ± 469.5 g, respectively, p < 0.01). Conclusions: Our data show the effectiveness of 28 mg and 14 mg LI on maternal anemia prevention, as previously reported with FI 40 mg. LI has similar effects of higher doses of ferrous iron on maternal hematological parameters, thus allowing to reduce iron doses and side effects.